epidemiology of uterine cancer
TRANSCRIPT
Incidence
Estimated new cases and deaths from endometrial (uterine corpus)
cancer in the United States in 2015
New cases: 54,870.
Deaths: 10,170.
Most common gynecologic malignancy in the United States and
accounts for 6% of all cancers in women.
Cancer Facts and Figures 2015. Atlanta
American Cancer Society, 2015.
Developed countries
Most common malignancy of female genital tract
Fourth most common cancer in women
(Breast>Lung>Colorectal)
Developing countries
4-5 times lower rates
India & South-Asia with lowest rates
GLOBOCAN – 2012Estimated age standardized incidence and mortality rates:
women (INDIA)Incidence Mortality 5-year prevalence
SEER Stat Fact Sheets: Endometrial
Cancer
● Constitutes 3.2% of all new cancer cases
● 1.5% of all cancer deaths
● 5-years survival rate of 81.5%
Lifetime Risk of Developing Cancer: Approximately 2.7 percent of
women will be diagnosed with endometrial cancer at some point
during their lifetime, based on 2009-2011 data.
Prevalence of this cancer: In 2011, there were an estimated
610,804 women living with endometrial cancer in the United
States.
Surveillance, Epidemiology, and End Results Program
SURVIVAL For endometrial cancer, 67.9% are diagnosed at the local
stage.
The 5-year survival for localized endometrial cancer is 95.1%.
Overall 5-year survival rate is 81.5%.
(Based on data from SEER 18 2004-2010)
5-year relative survival rates in the US by FIGO stage
Stage 5-year survival rate
I-A 88%
I-B 75%
II 69%
III-A 58%
III-B 50%
III-C 47%
IV-A 17%
IV-B 15%
“Survival by stage of endometrial cancer”.
American cancer society. March 2014
Mortality
The percent of endometrial cancer deaths is
highest among women aged 65-74.
Median age at death is 71 years
SEER 18 U.S. 2007-2011, All Races, Females
Risk factors
CHARACTERISTICS RELATIVE RISK
Nulliparity 2-3
Late Menopause (>52years) 2.4
Obesity (21-50 lb overweight ) 3
Obesity (>50 lb overweight) 10
Diabetes Mellitus 2.8
Unopposed Estrogen Therapy 4 - 8
Tamoxifene 2 .3
Atypical Endometrial Hyperplasia 8 - 29
Lynch II Syndrome 20
ROLE OF ESTROGEN Estrogen stimulation – growth & proliferation of endometrium
Progesterone (Corpus luteum) – inhibits proliferation of the
endometrium & stimulates secretions in the glands &
predecidual changes
Continuous estrogen stimulation of the endometrium bypasses
the normal recycling of the endometrium.
Transitions in women’s life – with absence of ovulation
predisposes to unopposed estrogen stimulation e.g. menarche,
menopause, PCOS & obesity.
ESTROGENS
Mitogenic effect on
endometrium
Higher rate of proliferation
Increased frequency of
Spontaneous mutations
Presence of estrogens may
facilitate “Clonal
expansion” of the genetic
damage occurred
PROGESTINS
Down regulate estrogen
receptor levels
Decrease proliferation
Increase Apoptosis
TAMOXIFENE
selective estrogen receptor modulators or SERMs.
acts like estrogen on some tissues in the body, such as the
uterus,
Blocks the effects of estrogen on other tissues, such as
the breast.
Used to prevent breast cancer in women who are at high risk
for the disease.
Relative risk of 2-3 for development of endometrial cancer while
receiving Tamoxifene
Obesity
Peripheral conversion of androgens secreted in adrenals &
ovaries into estrone (by the enzyme aromatase).
Amount of body fat – associated with decreased circulating
levels of both progesterone & Sex- hormone binding
globulin (SHBG).
Lower SHBG – Higher endogenous production of non-
protein bound estradiol.
PROTECTIVE FACTORS Combination oral contraceptives
(0.5 relative risk when used at least for 12months)
Addition of progestin appears to be protective
PROTECTIVE FACTORS Physical activity
Pregnancy and breast-feeding
Diet
low in saturated fats and high in fruits and vegetables
soy - based foods
Smoking – Lowers estrogen & protects against endometrial cancer
(But cannot be encouraged as a protective measure for obvious reasons)
Molecular PathogenesisTYPE I
(Endometrioid)
TYPE II
(Non - Endometrioid)
75% - 85% cases 15%
Younger women Older women
Perimenopausal Postmenopausal
H/o Unopposed Estrogen Therapy Without Estrogenic stimulus
Better differentiated Less differentiated
More favorable prognosis Poorer prognosis
Microsatellite instability & mutation in PTEN, PIK3CA, K - ras &
β - catenins
P-53 mutations & chromosome instability
TCGA – The Cancer Genome Atlas Project
Four broad categories of endometrial cancers were identified
1. Microsatellite instability cancers :
• Predominantly Endometrioid tumors.
• Mutation rates 10 fold higher
• Frequent K-ras mutation
2. Microsatellite stable cancers – Low CNV:
• High frequency mutation in beta-catenins (CTNNB1-
involved in cell-cell adhesions & WNT Signaling
pathway
TCGA – The Cancer Genome Atlas Project
3. Microsatellite stable cancers – High CNV:
• Frequent TP53 mutations
• Serous & Grade 3 Endometrioid tumors
• Share molecular features with High grade serous ovarian ca
& basal like breast Ca
4. Ultrahigh mutation rate cancers (more than 100 fold) –
• Mutation in POLE – a catalytic subunit of DNA polymerase
epsilon
• Also been associated in colorectal cancers.
LYNCH SYNDROME
In the United States, about 140,000 new cases of colorectal
cancer are diagnosed each year. Approximately 3 to 5
percent of these cancers are caused by Lynch syndrome.
Characterized by an increased risk for colon cancer and
cancers of the endometrium, ovary, stomach, small
intestine, hepatobiliary tract, urinary tract, brain, and skin.
LYNCH SYNDROME
Hereditary Non - Polyposis Colorectal cancer (HNPCC)
Autosomal dominant pattern of inheritance
caused by a germline mutation (i.e. pathogenic variant
in the germline) in a mismatch repair genes (MSH2,MLH1
MSH6, MSH3, PMS1 & PMS 2) and associated with tumors
exhibiting microsatellite instability (MSI).
Most cases result from alterations in MSH2 and MLH 1
Loss of mismatch repair
Mutator Phenotype
Accumulation of genetic mutations
through out the genome (in repetitive
DNA sequences -MICROSATELLITES )
Accumulation of Mutations in
Tumor-suppressor gene
Accelerated malignant
transformation
LYNCH SYNDROME – Genetic screening
Analysis of cancers for microsatellite instability
MSI (Microsatellite instability) seen in >90% of colonic
cancers % in >75% of endometrial cancers
Overall only 20%-25% of endometrial cancers exhibit MSI -
Majority of cases – Silencing of MLH 1 gene because of a
promoter methylation rather than germline mutation.
LYNCH SYNDROME
Following life time risks for cancer are seen:
o 52%-82% for colorectal cancer (mean age at diagnosis 44-61 years);
o 25%-60% for endometrial cancer in women (mean age at diagnosis
48-62 years);
o 6% to 13% for gastric cancer (mean age at diagnosis 56 years); and
o 4%-12% for ovarian cancer (mean age at diagnosis 42.5 years;
approximately 30% are diagnosed before age 40 years).
Mean age of onset of endometrial cancer – Before
menopause(often before 40years)
Clinical features are similar to the sporadic cases.
Well differentiated & Endometrioid type & early stages.
Survival is approximately 90%
SURVEILLANCE & PREVENTION IN
HIGH RISK POPULATION
Annual
Pelvic examination
Transvaginal Ultrasound
Endometrial biopsy – Beginning from 30 -35years of Age.
Guidelines for the clinical management of Lynch syndrome (HNPCC)
J Med Genet 2007; 44:353 – 362
Role of hysterectomy!!